EP0770615A1 - Verfahren zur Herstellung von Dihalogenazolopyrimidinen - Google Patents

Verfahren zur Herstellung von Dihalogenazolopyrimidinen Download PDF

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Publication number
EP0770615A1
EP0770615A1 EP96307528A EP96307528A EP0770615A1 EP 0770615 A1 EP0770615 A1 EP 0770615A1 EP 96307528 A EP96307528 A EP 96307528A EP 96307528 A EP96307528 A EP 96307528A EP 0770615 A1 EP0770615 A1 EP 0770615A1
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EP
European Patent Office
Prior art keywords
alkyl
process according
alkoxy
haloalkoxy
halogen
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Granted
Application number
EP96307528A
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English (en)
French (fr)
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EP0770615B1 (de
Inventor
Günther Krummel
Karl-Otto Stumm
Klaus-Jürgen Pees
Peter Heinz Rudi Liers
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BASF SE
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American Cyanamid Co
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Publication date
Application filed by American Cyanamid Co filed Critical American Cyanamid Co
Priority to SI9630630T priority Critical patent/SI0770615T1/xx
Publication of EP0770615A1 publication Critical patent/EP0770615A1/de
Application granted granted Critical
Publication of EP0770615B1 publication Critical patent/EP0770615B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • Dihaloazolopyrimidines are useful as intermediates in the preparation of a variety of agrochemical and pharmaceutical compounds.
  • 5,7-dihalo-6-aryl-1,2,4-triazolo[1,5-a]pyrimidines are key intermediates in the preparation of fungicidal triazolopyrimidine derivatives which are described in EP-A2-550113.
  • EP-A2-550113 describes a method for the preparation of 5,7-dihalo-6-aryl-1,2,4-triazolo[1,5-a]pyrimidines from malonic acid esters and 3-amino-1,2,4-triazole. However, that method is not entirely satisfactory because those pyrimidine compounds are obtained in low yield.
  • Makisumi discloses that the reaction could be carried out in the presence of sodium ethoxide in ethanol, and that the product dihydroxytriazolopyrimidine could be converted to the corresponding dichlorotriazolopyrimidine using a large excess of phosphorus oxychloride.
  • Makisumi's method is not entirely satisfactory for the preparation of dihaloazolopyrimidines because a large excess of phosphorus oxychloride is required and the overall yield of the reactions starting from diethyl malonate is often low.
  • the present invention provides an effective and efficient process for the preparation of a dihaloazolopyrimidine having the structural formula I wherein
  • the present invention also provides an effective and efficient process for the preparation of a dihydroxyazolopyrimidine having the structural formula IV wherein R, X, Y and Z are as described above.
  • This product (IV) is produced by the above-described procedure wherein the intermediate salt is acidified; the product (IV) then may be isolated, if desired.
  • a malonic acid ester represented by formula II is reacted with at least about one molar equivalent of a heterocyclylamine represented by formula III, preferably in a temperature range of about 120°C to 200°C, more preferably about 150°C to 180°C, and optionally in the presence of a base and/or solvent to form an intermediate salt.
  • the intermediate salt is halogenated with at least about two molar equivalents of phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride or phosphorus pentabromide, or a suitable mixture thereof, preferably in a temperature range of about 120°C to 150°C.
  • dihaloazolopyrimidines may be obtained in high yield and good purity by the effective and efficient process of the present invention.
  • dihaloazolopyrimidines are obtained in comparatively low yield when prepared according to art methods.
  • a further advantage of the present invention is that the inventive process may be conducted in one pot when the intermediate salt is not acidified.
  • a one pot reaction sequence is highly desirable because it avoids the isolation of intermediate compounds and significantly reduces the amount of chemical waste produced.
  • the intermediate salt is prepared in the presence of added base.
  • the base is preferably pres in an amount of at least about one molar equivalent relative to the malonic acid ester.
  • Bases suitat use in the process of the present invention int tertiary amines such as tri(C 2 -C 6 alkyl)amines substituted pyridines, quinoline, substituted quinolines, and ureas; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide and magnesium hydroxide; alkali metal C 1 -C 6 alkoxides such as sodium ethoxide and potassium tert -butoxide; alkaline earth metal C 1 -C 6 alkoxides such as magnesium ethoxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; and alkaline earth metal carbonates such as calcium carbonate.
  • Preferred bases include tri(C 2 -C 6 alkyl)amines such as triethylamine and tributylamine, pyridine, 4-(N,N-dimethylamino)pyridine, quinoline, and N,N,N',N'-tetramethylurea with triethylamine and tributylamine being more preferred.
  • the intermediate salt of this invention is represented by structural formula V when prepared in the absence of added base, and structural formula VI when prepared in the presence of added base: wherein R, X, Y and Z are as described above and "Base" represents the added base.
  • a solvent is present.
  • Solvents suitable for use in the process of the present invention have a boiling point of at least about 80°C and include aromatic hydrocarbons such as mesitylene, toluene, xylenes and mixtures thereof; chlorinated aromatic hydrocarbons such as mono- and dihalobenzenes and mixtures thereof; polynuclear aromatic hydrcarbons such as naphthalene, alkylnaphthalenes and mixtures thereof; alcohols such as butanol; and mixtures thereof.
  • the solvent of the present invention preferably has a boiling point range of about 80°C to 220°C, more preferably about 120°C to 180°C.
  • Mesitylene is one of the preferred solvents of the present invention.
  • the reaction between the malonic acid ester and the hetercyclylamine is preferably performed at a pressure of about one atmosphere or higher. If the reaction includes a solvent having a boiling point (defined at normal atmospheric pressure) lower than the reaction temperature, the reaction pressure must be elevated so that the solvent boiling point is elevated to at least the reaction temperature.
  • an aqueous acid is used to acidify the intermediate salt.
  • Aqueous acids suitable for use include aqueous mineral acids such as hydro-chloric acid, hydrobromic acid and sulfuric acid, and aqueous organic acids such as trifluoroacetic acid with hydrochloric acid, hydrobromic acid, and sulfuric acid being preferred.
  • the halogenation reaction may comprise reacting the intermediate salt or the dihydroxyazolopyrimidine with a suitable halogenating agent under conditions that produce the desired dihaloazolopyrimidine.
  • a suitable halogenating agent and conditions known in the art may be used.
  • the halogenating agent and conditions are those described herein for the preferred embodiments of the present invention.
  • the halogenation reaction may be conducted at atmospheric pressure or at a pressure greater than atmospheric pressure.
  • a suitable mixture thereof as used in the specification and claims with regard to the halogenating agents described herein, is defined as a phosphorus oxychloride and phosphorus pentachloride mixture or a phosphorus oxybromide and phosphorus pentabromide mixture.
  • the process of the present invention is especially useful for the preparation of dihaloazolopyrimidines wherein
  • the present invention is particularly useful for the preparation of 5,7-dihalo-6-aryl-1,2,4-triazolo[1,5-a]pyrimidines of formula I wherein
  • the process of the present invention can produce surprisingly high yields of dihydroxyazolopyrimidines and dihaloazolopyrimidines.
  • One key factor is the temperature of the reaction between the malonic acid ester and the heterocyclylamine.
  • the use of a base and/or solvent may also enhance the yield in some embodiments.
  • a mixture of 3-amino-1,2,4-triazole (12.6 g, 0.15 mol), diethyl (2-chloro-6-fluorophenyl)malonate (47.6 g, 0.15 mol), and tributyl amine (27.8 g, 0.15 mol) is heated at 170°C while allowing ethanol generated during the reaction to distill off. After 2 hours, residual ethanol is removed with a slow nitrogen stream for 30 minutes. The reaction mixture is then cooled to 130°C and phosphorus oxychloride (69 g, 0.45 mol) is added dropwise over 20 minutes.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP96307528A 1995-10-27 1996-10-16 Verfahren zur Herstellung von Dihalogenazolopyrimidinen Expired - Lifetime EP0770615B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
SI9630630T SI0770615T1 (en) 1995-10-27 1996-10-16 Process for the preparation of dihaloazolopyrimidines

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US802295P 1995-10-27 1995-10-27
US8022 1995-10-27

Publications (2)

Publication Number Publication Date
EP0770615A1 true EP0770615A1 (de) 1997-05-02
EP0770615B1 EP0770615B1 (de) 2003-06-18

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP96307528A Expired - Lifetime EP0770615B1 (de) 1995-10-27 1996-10-16 Verfahren zur Herstellung von Dihalogenazolopyrimidinen

Country Status (22)

Country Link
US (1) US5808066A (de)
EP (1) EP0770615B1 (de)
JP (1) JP4018182B2 (de)
KR (1) KR100443182B1 (de)
AR (1) AR004122A1 (de)
AT (1) ATE243211T1 (de)
BR (1) BR9605258A (de)
CA (1) CA2188905C (de)
DE (1) DE69628712T2 (de)
DK (1) DK0770615T3 (de)
ES (1) ES2202419T3 (de)
HU (1) HU217773B (de)
IL (1) IL119496A (de)
MX (1) MX9604882A (de)
PT (1) PT770615E (de)
RU (1) RU2147584C1 (de)
SG (1) SG55239A1 (de)
SI (1) SI0770615T1 (de)
SK (1) SK284071B6 (de)
TR (1) TR199600792A2 (de)
UA (1) UA48132C2 (de)
ZA (1) ZA968957B (de)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6117865A (en) * 1998-09-10 2000-09-12 American Cyanamid Company Fungicidal trifluorophenyl-triazolopyrimidines
US6117876A (en) * 1997-04-14 2000-09-12 American Cyanamid Company Fungicidal trifluorophenyl-triazolopyrimidines
US6242451B1 (en) * 1998-09-25 2001-06-05 Klaus-Juergen Pees Fungicidal trihalophenyl-triazolopyrimidines
US6559151B2 (en) 2000-05-08 2003-05-06 Basf Aktiengesellschaft 6-(2-trifluoromethyl-phenyl)-triazolopyrimidines
EP1359150A2 (de) * 1998-02-11 2003-11-05 Basf Aktiengesellschaft Verfahren und Zwischenprodukte zur Herstellung von fungiziden 7-Alkyltriazolopyrimidinen
WO2005056560A1 (en) * 2003-12-08 2005-06-23 Wyeth Process for the preparation of tubulin inhibitors
WO2005061502A1 (de) * 2003-12-19 2005-07-07 Basf Aktiengesellschaft 6-(aminocarbonyl-phenyl)-triazolopyrimidine, verfahren zu ihrer herstellung und ihre verwendung zur bekämpfung von schadpilzen sowie sie enthaltende mittel
WO2005087772A1 (de) * 2004-03-10 2005-09-22 Basf Aktiengesellschaft 5,6-dialkyl-7-amino-triazolopyrimidine, verfahren zu ihrer herstellung und ihre verwendung zur bekämpfung von schadpilzen sowie sie enthaltende mittel
WO2005087773A1 (de) * 2004-03-10 2005-09-22 Basf Aktiengesellschaft 5,6-dialkyl-7-amino-triazolopyrimidine, verfahren zu ihrer herstellung und ihre verwendung zur bekämpfung von schadpilzen sowie sie enthaltende mittel
US7038047B2 (en) 2001-07-18 2006-05-02 Basf Aktiengesellschaft Substituted 6-(2-methoxyphenyl) triazolopyrimides as fungicides
US7148227B2 (en) 2002-03-21 2006-12-12 Basf Aktiengesellschaft Fungicidal triazolopyrimidines, methods for producing the same, use thereof for combating harmful fungi and agents containing said substances
WO2007000412A1 (de) * 2005-06-27 2007-01-04 Basf Aktiengesellschaft Verfahren zur herstellung von substituierten phenylmalonestern, zwischenverbindungen sowie deren verwendung zur herstellung von 5 , 7-dihydr0xy-6- (2,4, 6-trifluorphenyl) -(1,2 , 4) triazolo (1 , 5-a) pyrimidinen
US7211545B2 (en) 2001-09-04 2007-05-01 Sumitomo Chemical Company, Limited Imidazo[1,2-a]pyrimidine and fungicidal compositions containing thereof
US7300908B2 (en) 2001-07-05 2007-11-27 Basf Aktiengesellschaft Fungicidal triazolopyrimidines, method for the production thereof and use thereof in controlling noxious fungi and agents containing said compounds
US7307172B2 (en) 2001-07-26 2007-12-11 Basf Aktiengesellschaft 7-amino triazolopyrimidines for controlling harmful fungi
WO2008084082A1 (de) * 2007-01-11 2008-07-17 Basf Se Verfahren zur herstellung arylsubstituierter anellierter pyrimidine
US8343977B2 (en) 2009-12-30 2013-01-01 Arqule, Inc. Substituted triazolo-pyrimidine compounds

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US6380202B1 (en) * 1998-09-25 2002-04-30 Basf Aktiengesellschaft Fungicidal fluoro-substituted 7-heterocyclyl-triazolopyrimidines
US6156925A (en) * 1998-09-25 2000-12-05 American Cyanamid Company Process for the preparation of halogenated phenylmaloates
US7683071B2 (en) * 2000-07-26 2010-03-23 Taro Pharmaceuticals Industries Ltd. Composition and method for improved bioavailability and enhanced brain delivery of 5,5-diphenyl barbituric acid
US6756379B2 (en) * 2001-07-26 2004-06-29 Taro Pharmaceutical Industries Ltd. Non-sedating barbiturate compounds as neuroprotective agents
US6939873B2 (en) * 2000-07-26 2005-09-06 Taro Pharmaceuticals Industries Limited Non-sedating barbituric acid derivatives
DE10063115A1 (de) * 2000-12-18 2002-06-27 Bayer Ag Triazolopyrimidine
JP2002249492A (ja) * 2000-12-22 2002-09-06 Nippon Bayer Agrochem Co Ltd トリアゾロピリミジン類
DE10121101A1 (de) * 2001-04-27 2002-10-31 Bayer Ag Triazolopyrimidine
CA2505335C (en) 2002-12-11 2013-09-10 Daniel Aaron Moros Method of treating movement disorders using barbituric acid derivatives
US7419982B2 (en) * 2003-09-24 2008-09-02 Wyeth Holdings Corporation Crystalline forms of 5-chloro-6-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine salts
WO2005030775A1 (en) * 2003-09-24 2005-04-07 Wyeth Holdings Corporation 6-[(substituted)phenyl]triazolopyrimidines as anticancer agents
JP4695595B2 (ja) * 2003-09-24 2011-06-08 ワイス・ホールディングズ・コーポレイション 抗癌剤としての６−アリール−７−ハロ−イミダゾ［１，２−ａ］ピリミジン類
DE102004007076A1 (de) * 2004-02-13 2005-08-25 Bayer Cropscience Ag Imidazolopyrimidine
PE20060020A1 (es) * 2004-03-30 2006-03-10 Basf Ag 5-6-cicloalquil-7-amino-triazolopirimidinas para combatir hongos fitopatogenos y procedimientos para su obtencion
WO2006003651A2 (en) * 2004-07-02 2006-01-12 Taro Pharmaceutical Industries, Ltd A process for preparing 1-methoxymethyl-5,5-diphenylbarbituric acid
JP2008532944A (ja) * 2005-03-01 2008-08-21 ビーエーエスエフ ソシエタス・ヨーロピア ５，６−ジアルキル−７−アミノアゾロピリミジン、それらの製造方法、有害な菌類を防除するためのそれらの使用、およびそれらの化合物を含む物質
CN101128465A (zh) * 2005-03-01 2008-02-20 巴斯福股份公司 5,6-二烷基-7-氨基唑并嘧啶、其制备方法及其在防治病原性真菌中的用途以及包含这些化合物的组合物
EP1856121A1 (de) * 2005-03-01 2007-11-21 Basf Aktiengesellschaft 5,6-dialkyl-7-amino-azolopyrimidine, verfahren zu ihrer herstellung und ihre verwendung zur bekämpfung von schadpilzen sowie sie enthaltende mittel
JP2008531656A (ja) * 2005-03-02 2008-08-14 ビーエーエスエフ ソシエタス・ヨーロピア ２−置換７−アミノアゾロピリミジン、それの製造方法および病原性菌類防除におけるそれの使用、ならびにその化合物を含む薬剤
JP2008532979A (ja) * 2005-03-10 2008-08-21 ビーエーエスエフ ソシエタス・ヨーロピア 有害菌類を防除するための４−アミノピリミジン類の使用、新規の４−アミノピリミジン類、それらを調製する方法およびそれらを含む組成物
CN101287695A (zh) * 2005-03-18 2008-10-15 巴斯福股份公司 制备5-卤代-2,4,6-三氟间苯二甲酸的方法
US20080200675A1 (en) * 2005-06-27 2008-08-21 Basf Aktiengesellschaft Method for Production of Substituted Phenylmalonate Esters, Novel Phenylmalonate Esters and Use Thereof
EP2081576A4 (de) * 2006-11-14 2010-06-30 Taro Pharmaceuticals North Ame Verfahren zur verbesserung der bioverfügbarkeit für nichtsedierende barbiturate

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Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6117876A (en) * 1997-04-14 2000-09-12 American Cyanamid Company Fungicidal trifluorophenyl-triazolopyrimidines
US6297251B1 (en) 1997-04-14 2001-10-02 American Cyanamid Co. Fungicidal trifluorophenyl-triazolopyrimidines
EP1359150A2 (de) * 1998-02-11 2003-11-05 Basf Aktiengesellschaft Verfahren und Zwischenprodukte zur Herstellung von fungiziden 7-Alkyltriazolopyrimidinen
EP1359150A3 (de) * 1998-02-11 2003-11-19 Basf Aktiengesellschaft Verfahren und Zwischenprodukte zur Herstellung von fungiziden 7-Alkyltriazolopyrimidinen
US6117865A (en) * 1998-09-10 2000-09-12 American Cyanamid Company Fungicidal trifluorophenyl-triazolopyrimidines
US6242451B1 (en) * 1998-09-25 2001-06-05 Klaus-Juergen Pees Fungicidal trihalophenyl-triazolopyrimidines
US6559151B2 (en) 2000-05-08 2003-05-06 Basf Aktiengesellschaft 6-(2-trifluoromethyl-phenyl)-triazolopyrimidines
US7300908B2 (en) 2001-07-05 2007-11-27 Basf Aktiengesellschaft Fungicidal triazolopyrimidines, method for the production thereof and use thereof in controlling noxious fungi and agents containing said compounds
US7038047B2 (en) 2001-07-18 2006-05-02 Basf Aktiengesellschaft Substituted 6-(2-methoxyphenyl) triazolopyrimides as fungicides
US7307172B2 (en) 2001-07-26 2007-12-11 Basf Aktiengesellschaft 7-amino triazolopyrimidines for controlling harmful fungi
US7211545B2 (en) 2001-09-04 2007-05-01 Sumitomo Chemical Company, Limited Imidazo[1,2-a]pyrimidine and fungicidal compositions containing thereof
US7148227B2 (en) 2002-03-21 2006-12-12 Basf Aktiengesellschaft Fungicidal triazolopyrimidines, methods for producing the same, use thereof for combating harmful fungi and agents containing said substances
WO2005056560A1 (en) * 2003-12-08 2005-06-23 Wyeth Process for the preparation of tubulin inhibitors
US7396835B2 (en) 2003-12-08 2008-07-08 Wyeth Process for the preparation of tubulin inhibitors
WO2005061502A1 (de) * 2003-12-19 2005-07-07 Basf Aktiengesellschaft 6-(aminocarbonyl-phenyl)-triazolopyrimidine, verfahren zu ihrer herstellung und ihre verwendung zur bekämpfung von schadpilzen sowie sie enthaltende mittel
WO2005087773A1 (de) * 2004-03-10 2005-09-22 Basf Aktiengesellschaft 5,6-dialkyl-7-amino-triazolopyrimidine, verfahren zu ihrer herstellung und ihre verwendung zur bekämpfung von schadpilzen sowie sie enthaltende mittel
WO2005087772A1 (de) * 2004-03-10 2005-09-22 Basf Aktiengesellschaft 5,6-dialkyl-7-amino-triazolopyrimidine, verfahren zu ihrer herstellung und ihre verwendung zur bekämpfung von schadpilzen sowie sie enthaltende mittel
EA009883B1 (ru) * 2004-03-10 2008-04-28 Басф Акциенгезельшафт 5, 6-диалкил-7-амино-триазолопиримидины, способ их получения и их применение для борьбы с патогенными растениями, а также содержащие их средства
EA010411B1 (ru) * 2004-03-10 2008-08-29 Басф Акциенгезельшафт 5,6-диалкил-7-аминотриазолопиримидины, способ их получения и их применение для борьбы с патогенными грибами, а также содержащие их средства
US9487519B2 (en) 2004-03-10 2016-11-08 Basf Se 5,6-Dialkyl-7-aminotriazolopyrimidines, their preparation and their use for controlling harmful fungi, and compositions comprising these compounds
WO2007000412A1 (de) * 2005-06-27 2007-01-04 Basf Aktiengesellschaft Verfahren zur herstellung von substituierten phenylmalonestern, zwischenverbindungen sowie deren verwendung zur herstellung von 5 , 7-dihydr0xy-6- (2,4, 6-trifluorphenyl) -(1,2 , 4) triazolo (1 , 5-a) pyrimidinen
WO2008084082A1 (de) * 2007-01-11 2008-07-17 Basf Se Verfahren zur herstellung arylsubstituierter anellierter pyrimidine
US8343977B2 (en) 2009-12-30 2013-01-01 Arqule, Inc. Substituted triazolo-pyrimidine compounds

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HUP9602957A2 (en) 1997-06-30
SK284071B6 (sk) 2004-09-08
HU217773B (hu) 2000-04-28
ATE243211T1 (de) 2003-07-15
JPH09124651A (ja) 1997-05-13
RU2147584C1 (ru) 2000-04-20
ZA968957B (en) 1998-04-24
EP0770615B1 (de) 2003-06-18
BR9605258A (pt) 1998-07-21
AR004122A1 (es) 1998-09-30
SI0770615T1 (en) 2003-12-31
HU9602957D0 (en) 1996-12-30
CA2188905C (en) 2005-12-06
CA2188905A1 (en) 1997-04-28
KR100443182B1 (ko) 2005-04-19
KR970021081A (ko) 1997-05-28
ES2202419T3 (es) 2004-04-01
HUP9602957A3 (en) 1998-01-28
UA48132C2 (uk) 2002-08-15
SK137796A3 (en) 1997-05-07
IL119496A (en) 2001-07-24
US5808066A (en) 1998-09-15
DE69628712T2 (de) 2004-04-29
SG55239A1 (en) 1998-12-21
MX9604882A (es) 1997-04-30
DE69628712D1 (de) 2003-07-24
PT770615E (pt) 2003-10-31
DK0770615T3 (da) 2003-07-14
TR199600792A2 (tr) 1997-05-21
IL119496A0 (en) 1997-01-10
JP4018182B2 (ja) 2007-12-05

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